Abstract In vitro and in vivo models of neurodegenerative disease such as Amyotrophic Lateral Sclerosis (ALS) have provided glimpses into the biological processes that go awry in these disorders. Current thinking indicates that major pathophysiologic processes include protein misfolding and accumulation, endoplasmic reticulum stress, dysfunctional intracellular trafficking, excitotoxicity, mitochondrial dysfunction, neuroinflammation, and abnormal RNA processing. The ARF family of GTP'ases are a phylogenetically- conserved family of proteins involved with membrane traffic, lipid metabolism/signaling, actin remodeling, and lipid droplet formation. Based on the apparent overlap between ALS pathophysiology and some of the biological actions of ARFs, we wondered if ARF signaling modified models of ALS. In recently published work we find that blocking activity of cytohesins (?Cy's?, ARF guanine nucleotide exchange factors) is neuroprotective. Understanding the cell biological mechanism of this observation is problematic because of the pleiotropic actions of Cy's and ARFs. The path forward will be facilitated by determining the specific Cy and specific ARF involved in this process as this will guide us to the relevant cell biological process. To this end, in specific aim #1, experiments will be undertaken to determine if inhibition of an individual Cy confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. In specific aim #2, experiments will be undertaken to determine if inhibition of an individual ARF confers protection against the toxic actions on motor neurons of mutant SOD or mutant TDP43. Identification of the specific Cy/ARF pair that upon disabling is neuroprotective will be the launching pad for insight into mechanisms and potential therapeutic targeting.